Incretin Drugs

Pancreatic Cancer Not Associated With Incretin Drugs

Study results indicate that risk increased similarly for all glucose lowering agents. Previous observational studies have linked incretin-based drugs such as GLP-1 mimetics and DPP4-inhibitors to an increased risk of pancreatic cancer. However, large trials such as SAVOR-TIMI and EXAMINE found no difference between DPP4-inhibitor treatment and placebo with regards to pancreatic cancer. Therefore, researchers conducted a study to examine the risk of pancreatic cancer with incretin-based drugs when compared with other glucose lowering agents. The study was a case-control study from 2005-2012 using population-based medical databases, which consisted of 6,036 pancreatic cancer cases and 60,360 controls. Odds ratios (OR) for pancreatic cancer associated with the use of incretin-based drugs and other glucose lowering agents were calculated using conditional logistic regression adjusting for other pancreatic cancer risk factors. A total of 122 patients with pancreatic cancer (2%) vs. 400 controls (0.7%) had used incretin-based drugs at least once, whereas 20.8% cases vs. 8.6% controls had used any glucose lowering agent. Compared with non-users of any glucose lowering agents, the adjusted risk of pancreatic cancer was increased for DPP4-inhibitor users (adjusted OR = 3.87, 95% CI 3.06-4.89) and GLP-1 mimetic users (adjusted OR=2.70, 95% CI 1.82-4.00). Furthermore, the adjusted OR for metformin users was 2.65 (95% CI 2.44-2.88), 2.65 (95% CI 2.41-2.91) for sulfonylurea users, and 3.61 (95% CI 3.24-4.03) for insulin users. Results indicate that the risk of pancreatic cancer was increased similarly for all glucose lowering agents, which suggests that diabetes is a risk factor for pancreatic cancer, independent of a specific drug effect. Practice Pearls Compared with non-users of
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A Multicenter Observational Study Of Incretin-based Drugs And Heart Failure

There is concern that antidiabetic incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, can increase the risk of heart failure. Ongoing clinical trials may not have large enough samples to effectively address this issue. We applied a common protocol in the analysis of multiple cohorts of patients with diabetes. We used health care data from four Canadian provinces, the United States, and the United Kingdom. With the use of a nested case–control analysis, we matched each patient who was hospitalized for heart failure with up to 20 controls from the same cohort; matching was based on sex, age, cohort-entry date, duration of treated diabetes, and follow-up time. Cohort-specific hazard ratios for hospitalization due to heart failure among patients receiving incretin-based drugs, as compared with those receiving oral antidiabetic-drug combinations, were estimated by means of conditional logistic regression and pooled across cohorts with the use of random-effects models. The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues. In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure,
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Incretin Mimetics For Type 2 Diabetes

Examples Generic Name Brand Name exenatide Bydureon, Byetta liraglutide Victoza Exenatide and liraglutide are a type of medicine called incretin mimetics used to treat people who have type 2 diabetes and who have not been able to control their blood sugar levels with oral medicines. This medicine is given as a shot. This medicine is also known as a glucagon-like peptide 1 (GLP-1) receptor agonist, or GLP-1 agonist. How It Works Incretin is a natural hormone that your body makes. It tells your body to release insulin after you eat. Insulin lowers blood sugar. Incretin mimetics act like (mimic) the incretins in your body that lower blood sugar after eating. Incretin mimetics: Prompt your pancreas to release insulin when blood sugar is rising. Prevent the pancreas from giving out too much glucagon. Glucagon is a hormone that causes the liver to release its stored sugar into the bloodstream. Help to slow the rate at which your stomach empties after eating. This may make you feel less hungry and more satisfied after a meal. Your blood sugar shouldn't get too high too fast after a meal. Why It Is Used These medicines help to keep blood sugar in a target range without causing low blood sugar or weight gain, unless they are taken in combination with medicines that do. Some people feel less hungry and lose weight while taking these medicines. How Well It Works Type 2 diabetes is a disease that can get worse over time, so medicines may need to change. Diabetes medicines work best for people who are being active and eating healthy foods. Studies have suggested that incretin mimetics lower hemoglobin A1c by 0.5% to 1%.1 All medicines have side effects. But many people don't feel the side effects, or they are able to deal with them. Ask your pharmacist about the side effects of each
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More About Incretin-based Diabetes Drugs And Heart Failure

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[incretin Mimetic Drugs: Therapeutic Positioning].

Abstract Type 2 diabetes is a chronic and complex disease, due to the differences among affected individuals, which affect choice of treatment. The number of drug families has increased in the last few years, and these families have widely differing mechanisms of action, which contributes greatly to the individualization of treatment according to the patient's characteristics and comorbidities. The present article discusses incretin mimetic drugs. Their development has been based on knowledge of the effects of natural incretin hormones: GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and dipeptidyl peptidase enzyme 4 (DPP4), which rapidly degrade them in the systemic circulation. This group is composed of 2 different types of molecules: GLP-1 analogs and DPP4 enzyme inhibitors. The benefits of these molecules include a reduction in plasma glucose without the risk of hypoglycemias or weight gain. There are a series of questions that require new studies to establish a possible association between the use of these drugs and notification of cases of pancreatitis, as well as their relationship with pancreatic and thyroid cancer. Also awaited is the publication of several studies that will provide information on the relationship between these drugs and cardiovascular risk in people with diabetes. All these questions will probably be progressively elucidated with greater experience in the use of these drugs. KEYWORDS: Agonistas del receptor de GLP-1; Dipeptidyl dipeptidase-4 inhibitors; GLP-1 receptor antagonists; Incretinas; Incretins; Inhibidores de la enzima dipeptildipeptidasa 4 (iDPP4)
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Abstract Type 2 diabetes in East Asians is characterized primarily by β-cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted in response to meal ingestion, and enhance insulin secretion glucose-dependently. Incretin-based drugs, dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists, that ameliorate β-cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta-analyses of clinical trials on DPP-4i and glucagon-like peptide-1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β-cell dysfunction. In addition, we found increased glycated hemoglobin-lowering effects of DPP-4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP-4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP-4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin-associated hypoglycemia by DPP-4i has gained attention with regard to the enhancement of hypoglycemia-induced glucagon secretion by insulinotropic polypept
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Incretin Mimetics (glp-1 Agonists)

Tweet Incretin mimetics are a relatively new group of injectable drugs for treatment of type 2 diabetes. The drugs, also commonly known as glucagon-like peptide 1 (GLP-1) receptor agonists or GLP-1 analogues, are normally prescribed for patients who have not been able to control their condition with tablet medication. Drugs in this class In the UK, the following incretin mimetics are available for type 2 diabetic patients - (trade name first, generic name in brackets): Bydureon (Exenatide) - taken once weekly Byetta (Exenatide) - taken twice daily Lyxumia (lixisenatide) - taken once daily Trulicity (Dulaglutide) - taken once weekly Victoza (Liraglutide) - taken once daily Byetta and Bydureon are the same medical drug. The only difference is that Bydureon is long-lasting, requiring only one injection per week, whereas Byetta is taken twice-daily due to its much shorter-term effects. How do they work? They work by copying, or mimicking, the functions of the natural incretin hormones in your body that help lower post-meal blood sugar levels. These functions include: Stimulating the release of insulin by the pancreas after eating, even before blood sugars start to rise. Inhibiting the release of glucagon by the pancreas. Glucagon is a hormone that causes the liver to release its stored sugar into the bloodstream. Slowing glucose absorption into the bloodstream by reducing the speed at which the stomach empties after eating, thus making you feel more satisfied after a meal. These effects are in direct response to the presence of carbohydrate in the gut and therefore the chance of significant hypoglycemia occurring is unlikely, unless used in combination with other hypoglycemic drugs. Benefits of incretin mimetics By increasing insulin secretion and inhibiting glucagon releas
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Incretin-based Drugs

DRUG RECORD The incretins are gastrointestinal polypeptide hormones that act to modulate insulin secretion from pancreatic beta cells. These hormones include glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), and they are secreted from the upper gastrointestinal tract in response to feeding. They act on the pancreas, causing insulin release even before blood glucose levels are elevated. Both hormones are polypeptides that are rapidly cleared from the serum by the enzyme dipeptidyl peptidase-4 (DPP-4). The incretin pathway provides several potential targets for therapy of type 2 diabetes, the main ones being DPP-4 inhibitors and GLP-1 analogues. These incretin-based hypoglycemic agents are relatively new and they have not been implicated as common causes of drug induced liver injury. These two groups of incretin-based drugs are quite different in chemical structure, pharmacology and safety profile and are discussed separately. Drugs in the Subclass, Incretin-Based Drugs: DRUG CAS REGISTRY NUMBER Alogliptin 850649-62-6 C18-H21-N5-O2.C7-H6-O2
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Incretin Mimetic Drugs For Type 2 Diabetes

Drugs in the incretin mimetic class include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). These drugs work by mimicking the incretin hormones that the body usually produces naturally to stimulate the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.
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Type 2 diabetes mellitus (T2DM) is a huge health problem globally. It affects nearly 25.8 million people in the United States.1 Over 35% of US adults 20 years or older (or 79 million Americans) are currently classified as having prediabetes, which places them at greater risk for developing diabetes. Patients diagnosed with diabetes have a much higher risk of developing heart disease, hypertension, stroke, and kidney disease.1 No optimal medication exists currently for the treatment of T2DM. The American Diabetes Association (ADA) recommends metformin as the preferred initial pharmacologic agent for the treatment of this disease. However, if high doses of noninsulin monotherapy are not successful at achieving a patient’s goal glycated hemoglobin (A1C), then a second oral agent, a glucagonlike peptide-1 (GLP-1) receptor agonist or insulin should be added. Many patients will eventually need to have insulin added to their medication regimen.2 Numerous side effects exist with all medications used for the treatment of T2DM, including hypoglycemia and weight gain, as well as difficulty tolerating therapy.2 Some of the more recent classes of medications for the treatment of T2DM focus on the incretin or GLP-1 system. GLP-1 based therapies have not been studied in patients with type 1 diabetes (T1DM) and therefore should not be used in those patients at this time. The goal in the treatment of patients with T2DM is to restore normoglycemia both fasting and postprandially. Incretin Effect To understand how the medications affecting the incretin system work, it is necessary to first understand the incretin effect. When nondiabetic patients are given oral glucose, their insulin levels increase as much as 3 times greater than when the same patients are given IV glucose to match the
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Side Effects Of Incretin Mimetics (glp-1 Agonists)

Incretin Mimetics: How they work Incretins are protein hormones produced in the digestive tract after we have eaten a meal. They lead to an increase in insulin secretion, so the sugar from the meal can be delivered from our blood into our cells, reducing blood sugar levels. Incretin mimetics ‘mimic’ the incretin called GLP-1, so they too lower blood sugar. You need inject incretin mimetics, also known as GLP-1 agonists, under your skin, just before a meal. Side effects of Incretin Mimetics or GLP-1 drugs may be the result of the way they work in the human body. Incretin Mimetics lower blood sugar in the human body by: Increasing insulin secretion from the pancreas after a meal Reducing the amount of glucagon secreted from the pancreas. Glucagon is a hormone that signals the liver to release stored sugar into the blood stream Reducing the speed at which food is ‘emptied’ into the intestine. This helps you feel fuller for longer and reduces appetite. Incretin Mimetics: Most Prescribed brands Three incretin mimetics are most prescribed and sold: Exenatide (Immediate Release), which was the first in this class of drugs and sold under the brand name Byetta Exenatide (Long Acting), sold under the brand name Bydueron Liraglutide, sold under the trade name, Victoza Other commonly available brand names are Saxenda and Trulicity. Exenatide is isolated from the saliva of a lizard called Heloderma suspectum. (popularly called the Gila Monster). Exenatide (Immediate Release) or Byetta is sold as as a solution (liquid) in a prefilled dosing pen. You need to inject it just under the skin twice a day, just before meals. It should never be injected after meals. Your doctor will probably start you on a low dose of Exenatide (Immediate Release) and may switch you a higher dose if
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Incretin-based Therapies For The Treatment Of Type 2 Diabetes: Evaluation Of The Risks And Benefits

Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia arising from a combination of insufficient insulin secretion together with resistance to insulin action. The incidence and prevalence of type 2 diabetes are rising steadily, fuelled in part by a concomitant increase in the worldwide rates of obesity. As longitudinal studies of type 2 diabetes provide evidence linking improved glycemic control with a reduction in the rates of diabetes-associated complications, there is considerable interest in the therapy of type 2 diabetes (Fig. 1), with a focus on the development and use of new agents that exhibit improved efficacy and safety relative to current available medicines. Although the number of patients with type 2 diabetes that successfully achieve target levels of A1C is steadily improving, a substantial number of subjects continue to fall short of acceptable treatment goals, leaving them at high risk for development of diabetes-associated complications (1). More importantly, a large number of subjects with type 2 diabetes fail to achieve target values for glucose, lipids, and blood pressure, with only 12.2% of patients meeting target values despite recent improvements in therapeutic agents targeting hyperglycemia, dyslipidemia, and hypertension (2). The development of multiple new agents for the treatment of type 2 diabetes has broadened the options for patient-specific therapy. However, no currently available agents exhibit the ideal profile of exceptional glucose-lowering efficacy to safely achieve target levels of glycemia in a broad range of patients. Hence, highly efficacious agents that exhibit unimpeachable safety, excellent tolerability, and ease of administration to ensure long-term adherence and that also clearly reduce common comorbi
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Incretin Based Treatments

Incretin based treatments reduce post meal blood sugars. These medicines are also euglycemics, which help return the blood sugar to the normal range. When you have type 2 diabetes, the blood sugar may be too high after a meal, even if you eat very little carbohydrate (CHO). This, in part, is due to glucagon levels staying too high after meals. Medicines, called incretin based treatments, are now available to control post-meal glucagon, and help reduce the post meal blood sugars. These medicines also are blood sugar normalizing medications or euglycemics (drugs that help return the blood sugar to the normal range). The incretin based medicines are available in two families of medicines: DPP-4 Inhibitors and GLP-1 analogs. Sitagliptin, saxagliptin, and linagliptin (approved May 2011 and is not available yet) are DPP-4 inhibitors and are taken as pills. Exenatide and liraglutide are GLP-1 analogs and are taken by injection. If you have kidney problems, the dose of the incretin based medicines may need to be adjusted. Please tell your doctor if you have kidney problems before starting these medicines. DPP-4 Inhibitors DPP-4 inhibitors are oral medicines for people with type 2 diabetes that help control blood sugar levels, especially after eating. After eating, your gut naturally releases hormones—two important ones are GLP-1 and GIP. These hormones increase insulin release to help control blood sugar levels. GLP-1 also decreases glucagon release at meals, to further control blood sugar levels. However, these hormones are quickly broken down in the body by an enzyme called DPP-4. DPP-4 inhibitors like sitagliptin and saxagliptin block DPP-4 from breaking down GLP-1 as quickly so that GLP-1 can have a longer effect in the body. While DPP-4 inhibitors may be used as an initi
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Incretin

GLP-1 and DPP-4 inhibitors Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. They also inhibit glucagon release from the alpha cells of the islets of Langerhans. The two main candidate molecules that fulfill criteria for an incretin are the intestinal peptides glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (also known as: glucose-dependent insulinotropic polypeptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4); both GLP-1 and GIP are members of the glucagon peptide superfamily.[1][2][3] "Many factors stimulate insulin secretion, but the main one is blood glucose. Incretins, especially GIP and GLP-1 secreted, respectively, by K and L cells in the gut are also important" (Rang and Dale's Pharmacology (2015)). GLP-1 (7-36) amide is not very useful for treatment of type 2 diabetes mellitus, since it must be administered by continuous subcutaneous infusion. Several long-lasting analogs having insulinotropic activity have been developed, and three, exenatide (Byetta) and liraglutide (Victoza), plus exenatide extended-release (Bydureon), have been approved for use in the U.S. The main disadvantage of these GLP-1 analogs is they must be administered by subcutaneous injection. Another approach is to inhibit the enzyme that inactivates GLP-1 and GIP, DPP-4. Several DPP-4 inhibitors that can be taken orally as tablets have been developed. Once weekly dosage of
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Incretin-based Therapies

Go to: INTRODUCTION (by M.A.N.) Incretin mimetics and inhibitors of the protease dipeptidyl peptidase (DPP)-4 are new classes of antidiabetic agents first introduced in the years 2005 (exenatide) and 2007 (sitagliptin), respectively. Both use the antidiabetic properties of the incretin hormone, glucagon-like peptide (GLP)-1 (1). This gut-derived peptide hormone not only augments glucose-induced insulin secretion (required to fulfill the definition of an incretin hormone), but does so in a highly glucose-dependent manner (2), thus preventing GLP-1 alone from provoking hypoglycemia. Additional beneficial effects of GLP-1 on endocrine pancreatic islets are that it 1) supports the synthesis of proinsulin to replenish insulin stores in β-cells; 2) reduces the rate of β-cell apoptosis when islets are incubated in a toxic environment (glucotoxicity, lipotoxicity, cytotoxic cytokines); and 3) promotes differentiation of precursor cells with the ability to develop into β-cells and proliferation of β-cell lines, and in whole animals (rodent studies), this leads to an increased β-cell mass within a few days or weeks (1,3). Furthermore, GLP-1 can lower glucagon concentrations, i.e., induce α-cells to respond again to the inhibitory action of hyperglycemia, while leaving the counterregulatory glucagon responses undisturbed, as in the case of hypoglycemia (2,4). Additional activities of GLP-1 are the deceleration of gastric emptying (5), which slows the entry of nutrients into the circulation after meals, a reduction in appetite, and earlier induction of satiety (6), leading to weight reduction with chronic exposure (7). Renal effects (promotion of sodium and water excretion (8), as well as neuro- (9) and cardioprotective (10) properties of GLP-1, have also been described. Whil
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